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    Neurofibromatosis Type I (NF1) : Presented by Lei Du

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    Ikhdin Saadhi
    Neurofibromatosis Type 1 is a hereditary neurological disorder caused by a mutation in the NF1 gene. It affects 1 in 3,000 people and predisposes individuals to cancer development. The NF1 gene encodes neurofibromin, which acts as a tumor suppressor by regulating the Ras, cAMP, PKC, and mTOR pathways. Neurofibromatosis Type 1 can cause café-au-lait spots, Lisch nodules, skin neurofibromas, and tumors of the central nervous system.

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    Neurofibromatosis Type I (NF1) : Presented by Lei Du

    Uploaded by

    Ikhdin Saadhi
    35 views18 pages
    Neurofibromatosis Type 1 is a hereditary neurological disorder caused by a mutation in the NF1 gene. It affects 1 in 3,000 people and predisposes individuals to cancer development. The NF1 gene encodes neurofibromin, which acts as a tumor suppressor by regulating the Ras, cAMP, PKC, and mTOR pathways. Neurofibromatosis Type 1 can cause café-au-lait spots, Lisch nodules, skin neurofibromas, and tumors of the central nervous system.

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    neurofibrom

    Original Title

    3- NF1 Lei

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    Neurofibromatosis Type 1 is a hereditary neurological disorder caused by a mutation in the NF1 gene. It affects 1 in 3,000 people and predisposes individuals to cancer development. The NF1 gene encodes neurofibromin, which acts as a tumor suppressor by regulating the Ras, cAMP, PKC, and mTOR pathways. Neurofibromatosis Type 1 can cause café-au-lait spots, Lisch nodules, skin neurofibromas, and tumors of the central nervous system.

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    © All Rights Reserved
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    35 views18 pages

    Neurofibromatosis Type I (NF1) : Presented by Lei Du

    Uploaded by

    Ikhdin Saadhi
    Neurofibromatosis Type 1 is a hereditary neurological disorder caused by a mutation in the NF1 gene. It affects 1 in 3,000 people and predisposes individuals to cancer development. The NF1 gene encodes neurofibromin, which acts as a tumor suppressor by regulating the Ras, cAMP, PKC, and mTOR pathways. Neurofibromatosis Type 1 can cause café-au-lait spots, Lisch nodules, skin neurofibromas, and tumors of the central nervous system.

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    of 18

    Neurofibromatosis

    Type I (NF1)

    Presented by Lei Du
    What is Neurofibromatosis
    Type I?
     a hereditary neurological disorder
     affects 1 in 3,000 people world-wide
     Autosomal dominant with fully penetrant
     Caused by mutation in NF1 gene, codes for
    neurofibromin 1
     2-hit Hypothesis
     30~50% arises from sporadic mutations
     A common cancer-predisposing disease
    NF1 affects a variety of tissues

     Café-au-lait spots
     Lisch nodules in iris
     Skin Neurofibroma
     Plexiform neurofibroma
    www.science.room.net/.../Neurofibromotosis/
     Bony defects
     Tumors of the central nervous system.

    Variation in clinical features both inter and intra-familially


    Genetic Info:
     Cloned in 1990 using overlapping cDNA
    clones from the translocation breakpoint
    region (TBR) gene
     Encodes Neurofibromin 1
     on Chromosome 17

    http://ghr.nlm.nih.gov/dynamicImages/chromomap/nf1.jpeg
    Mutation rate is one of the highest
    of human disease genes

     Size: 2839 Amino Acid

     By comparison:
     Estimated average: ~300
     Rb gene: 928
     Ras gene: 1047

    www. wikimedia.org
    More than 1000 NF1
    mutations has been identified

     Single nucleotide
    substitutions
     Minor molecular lesions
     Large-scale genomic
    deletions
     Chromosomal instability
    http://www.tuxhausen.de/pic/ms_linux_pinguin_muta
    tionen.jpg
    Where is NF1 expressed?
     Ubiquitously expressed in a range of
    tissues such as bone and skin
     Greatest in cells with a neurological
    origin: schwann cells, neurons
     Also in karatinocytes and
    melanocytes

    http://news.bbc.co.uk/hi/english/static/in_depth/sci_tech/
    2000/human_genome/default.stm
    Animal Model: Mice
    Yang et al. (2006)

    NF1 acts in the Ras pathway!!!

     Homozygous die
     +/- fibroblasts increased proliferation, migration,
    and collagen synthesis
     -/- cells develop neurofibromas
     mice that carry linked germline mutations in Nf1 and
    p53 develop malignant peripheral nerve sheath
    tumors

    http://www.wildlifetrust.org.uk/cheshire/IMAGES/watch_harvest_mice.jpg
    In Ras Pathway:

    Lodish et al. Fig. 20-5


     Neurofibromin contains domain resembles GAP
     Encodes for a TUMOR SUPPRESSOR

    Lodish et al. Fig. 20-5


    Active Ras promote cell proliferation  Tumor
    http://219.221.200.61/ywwy/zbsw(E)/edetail6.htm
    Animal Model: Drosophila
     In Drosophila (Tong et al, 2007)

     Inactivation of NF1
     reduced life span and reproductive fitness
     increased vulnerability to heat

     reduced mitochondrial respiration

     Over-expression of NF1 Opposite result

    NF1 acts in the Adenylate


    Cyclase and cAMP pathway!!!

    http://farm1.static.flickr.com/31/54275159_1a756047cf.jpg
    NF1
    What is the function of NF1?

    1. Ras GTPase Activator Activity


    2. Adenylate cyclase and cAMP
    3. AKT-mTOR mediated pathways
    4. PKC pathway Cell mobility
    NF1: Lee & Stephenson (2007)
    Summary:

     Neurofibramatosis Type 1 is a hereditary


    neurocutaneous disorder that affects a variety
    of tissue types
     NF1 gene product is a tumor suppressor
     Mutation in both copies has cancer pre-
    disposing function
     It acts in many pathways: Ras, cAMP, PKC, &
    mTOR
     phenotypically dominant with full penetrant.
    Reference:
     http://www.genecards.org/cgi-
    bin/carddisp.pl?gene=NF1
     http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?b
    ook=gene&part=nf1
     http://www.upmc.edu/Neurofibro/NNFFconsortiu
    m.htm
     http://www.genetests.org/query?gene=NF1
     http://egp.gs.washington.edu/data/nf1/
     http://herkules.oulu.fi/isbn9514268040/html/i100
    0977.html
     http://www.ncbi.nlm.nih.gov/pubmed/2114220?d
    opt=Abstract&holding=npg

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